Rosiglitazone, a PPAR gamma agonist: potent promoter of hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers

International Journal of Cancer. Journal International Du Cancer
Ronald A LubetClinton J Grubbs

Abstract

In an initial study to determine if rosiglitazone had chemopreventive activity, Fischer-344 female rats were administered twice weekly doses of hydroxybutyl(butyl)nitrosamine (OH-BBN), a urinary bladder specific carcinogen, for 8 weeks. Two weeks following the last dose of OH-BBN, rats were administered rosiglitazone (50 mg/kg BW) daily by gavage for the remainder of the study (7 months). Only 57% of OH-BBN-treated animals developed palpable urinary bladder cancers during the course of the study, while all of the OH-BBN plus rosiglitazone treated rats developed large cancers (p < 0.01). Surprisingly, examination for PPAR gamma by immunohistochemistry in the urinary bladders of rats showed that while untreated bladder urothelium and preneoplastic lesions clearly expressed PPAR gamma, frank carcinomas exhibited significantly lower levels. This was confirmed by employing microarray studies of the same samples. In additional studies, lower doses of rosiglitazone (10, 2 and 0.4 mg/kg BW/day) were administered. The 10 mg/kg BW/day dose greatly enhanced bladder cancer incidence (p < 0.01). The dose of 2 mg/kg BW/day, which is roughly equivalent to a standard human dose, also significantly increased bladder cancer incidence (controls, ...Continue Reading

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